Malaria Vaccines: Pvs230D1-EPA and PvCSP

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The major challenges facing Pvs230D1-based TBV development are 1) preparation and successful filing of an Investigational New Drug application with the FDA, 2) demonstrating in a first-in-human study that Pvs230D1 is a suitable antigenic target to generate transmission-blocking antibodies, using a safe formulation that induces sustained high antibody responses, 3) developing the P. vivax blood stage challenge model at the NIH Clinical Trial Center including the successful filing of an IND application for use of the Australian P. vivax challenge agent and to produce two NIH P.vivax master cell banks, 4) COVID-19-related disruption to clinical center facility availability for bank manufacture and 5) demonstration of reliable mosquito transmission in bank validation clinical trials to permit assessment of transmission-blocking endpoints as part of PvTBV development. Using our chemical conjugation platform, Pvs230D1M has been chemically conjugated to EPA and the conjugated nanoparticle enhanced immunogenicity compared to the monomer in mice. The conjugated Pvs230D1M-EPA enhanced the antibody titers compared to the monomeric form. The antibodies raised against the conjugate reduced transmission of P. vivax to mosquitoes in the ex vivo membrane feeding assay. In FY18, a manufacturing campaign was initiated for the cGMP production of a Pvs230D1-EPA chemically conjugated vaccine for phase 1 human trials, with funds provided by OD, NIAID. The technical transfer process and cGMP manufacturing has been completed according to project timelines. In Q1 2021 approximately 2000 vials were filled and have been evaluated for identify, strength, quality and purity. The conjugated Pvs230D1M-EPA vials passed all regulated tests in accordance with prespecified parameters. The bulk drug substance, conjugated Pvs230D1M-EPA, has been shown to be stable under its current storage conditions. Preclinical development has been initiated using Matrix-MTM (Novavax, Gaithersburg, MD), a saponin based adjuvant. A GLP rabbit toxicology study was completed in Q2 2021 with conjugated Pvs230D1M-EPA/Matrix-M; no safety concerns were observed. Pooled antiserum obtained from the rabbit toxicology study was shown to have transmission reducing activity in ex vivo membrane feeding assays using P. vivax gametocytes obtained from a Saimiri monkey infected with P. vivax and using gametocytes from clinically P. vivax infected adult patients in Brazil. An agreement with Novavax to use Matrix-M adjuvant for the phase 1 clinical trial is anticipated. Phase 1 safety and immunogenicity trials in the US, and the parallel development of a P. vivax blood stage challenge model to produce gametocytes will facilitate assessment of preliminary transmission-blocking endpoints and accelerate product development prior to field studies. We report progress from the following publications in FY2023: Tebeje SK, Chali W, Hailemeskel E, Ramjith J, Gashaw A, Ashine T, Nebret D, Esayas E, Emiru T, Tsegaye T, Teelen K, Lanke K, Takashima E, Tsuboi T, Salinas ND, Tolia NH, Narum D, Drakeley C, Witkowski B, Vantaux A, Jore MM, Stone WJR, Hansen IS, Tadesse FG, Bousema T. Naturally acquired antibodies to gametocyte antigens are associated with reduced transmission of Plasmodium vivax gametocytes to Anopheles arabiensis mosquitoes. 2023. Front Cell Infect Microbiol. Jan 16. 12:1106369. doi: 10.3389/fcimb.2022.1106369. In work led at Radboud University, we and our partners investigated associations between antibody prevalence and P. vivax infectivity to mosquitoes. Antibodies against Pvs47, Pvs230 and Pvs25 were associated with 23 and 34% reductions in mosquito infection rates (p<0.0001), respectively. Individuals who showed evidence of transmission blockade in serum-replacement DMFAs (n=8) were significantly more likely to have PvsHAP2 or Pvs47 antibodies. Further studies may demonstrate causality for the observed associations, improve our understanding of the natural transmission of P. vivax and support vaccine development. Fantin RF, Coelho CH, Berhe AD, Magalhaes LMD, Pereira DB, Salinas ND, Tolia NH, Amaratunga C, Suon S, Sagara I, Narum DL, Abeijon C, Fujiwara RT, Bartholomeu DC, Campos-Neto A, Duffy PE, Bueno LL. Detection and immunological characterization of VIR protein family member VIR-14 in Plasmodium vivax-infected subjects. 2023. Frontiers in Immunology. Apr 7;17(4):e0011229. doi: 10.1371/journal.pntd.0011229. Plasmodium vivax is a major challenge for malaria control due to its wide geographic distribution, high frequency of submicroscopic infections, and ability to induce relapses due to the latent forms present in the liver (hypnozoites). This study investigated and characterized a P. vivax protein (PvVir14) for its role in parasite biology and its interactions with the immune system (ClinicalTrials.gov NCT00663546 & NCT02334462). We collected sera or plasma from P. vivax-infected subjects in Brazil (n = 121) and Cambodia (n = 55), and from P. falciparum-infected subjects in Mali (n = 28), to assess antibody recognition of PvVir14. Circulating antibodies against PvVir14 appeared in 61% and 34.5% of subjects from Brazil and Cambodia, respectively, versus none (0%) of the P. falciparum-infected subjects from Mali who have no exposure to P. vivax. IgG1 and IgG3 most frequently contributed to anti-PvVir14 responses. PvVir14 antibody levels correlated with those against other well-characterized sporozoite/liver (PvCSP) and blood stage (PvDBP-RII) antigens, which were recognized by 7.6% and 42% of Brazilians, respectively. When analyzed at a single-cell level, the B cell receptor gene hIGHV3-23 was only seen in subjects with active P. vivax infection where it comprised 20% of V gene usage. Specific B cell subsets, anti-PvVir14 circulating antibodies, and NKT cell levels declined after treatment of P. vivax. This study provides the immunological characterization of PvVir14, a unique P. vivax protein, and possible association with acute host's immune responses, providing new information of specific host-parasite interaction. Our unpublished progress during this reporting period includes the following advances: In FY22 LMIV completed its first clinical study (NCT05095272) to establish a P. vivax blood stage challenge model at the NIH Clinical Center. In this study two subjects underwent blood stage challenge and provided blood donations to manufacture two P. vivax master cell banks from which challenge agent will be derived in future studies, In FY23 the cGMP manufacture and associated documentation was completed for the Drug Master File that will accompany future IND human challenge studies using these master cell banks. Bank validation studies for the ongoing development of the P. vivax blood stage challenge model including optimization of human-to-mosquito transmission at the NIH Clinical Center are being planned for FY23/24. In FY23 LMIV also launched its first clinical study of Pvs230D1-EPA/Matrix M. Enrolment for this trial has started for first in human characterization of safety and immunogenicity.